SOLUBILITY ENHANCEMENT

TECHNIQUES

Presented by
Dr. Md. Faheem Haider
Assistant Professor
Faculty of Pharmacy, IU
CONTENTS:
 INTRODUCTION
 IMPORTANCE OF SOLUBILITY
 NEED OF IMPROVING SOLUBILITY
 TECHNIQUES OF SOLUBILITY ENHANCEMENT
 APPLICATIONS
 CONCLUSIONS
 REFERENCES
 INTRODUCTION

SOLUBILITY:
 The term ‘Solubility’ is defined as maximum amount of solute that can be
dissolved in a given amount of solvent to form a homogenous system at
specified temperature.

 The solubility of a drug is represented as parts, percentage, molarity, molality,

volume fraction, mole fraction.
The Indian pharmacopoeia provides general
terms to describe a solubility given range:
DEFINITION PARTS OF SOLVENT REQURIED
FOR ONE PART OF SOLUTE

Very soluble <1

Freely soluble 1-10

Soluble 10-30

Sparingly soluble 30-100

Slightly soluble 100-1000

Very slightly soluble 1000-10,000

insoluble >10,000
 IMPORTANCE OF
SOLUBILITY:
 Therapeutic effectiveness of a drug depends upon the
bioavailability and ultimately upon the solubility of drug molecules.
 Solubility is one of the important parameter to achieve desired
concentration of drug in systemic circulation for pharmacological
response to be shown.
 Currently only 8% of new drug candidates have both high solubility
and permeability.
 Low aqueous solubility is the major problem encountered with
formulation development of new chemical entities.
 Most of drugs are weakly acidic and weakly basic with poor
aqueous solubility. Hence various techniques are used for the
improvement of the solubility of poorly water-soluble drugs.
 NEED FOR SOLUBILITY
ENHANCEMENT:

 Less than 40% of lipophilic drugs candidates fail to reach market due to poor
bioavailability, even though these drugs might exhibit potential pharmaco-
dynamic activities.
 The lipophilic drug that reaches market requires a high dose to attain proper
pharmacological action.
 The basic aim of the further formulation & development is to make that drug
available at proper site of action within optimum dose.
PROCESS OF SOLUBILIZATION:

1) The separation of the molecule of the solvent to

provide space in the solvent for solute.

2) The breaking of intermolecular ionic bonds in

the solute.

3) The interaction between the solvent and the

solute molecule or ion.
 PROCESS OF SOLUBILIZATION:

Step 1: Holes opens in the solvent

Step 2:Molecules of the solid breaks away from the bulk

Step 3: The freed solid molecule is integrated into the hole in
the solvent.
TECHNIQUES OF
SOLUBILITY
ENHANCEMENT
I. Physical Modifications

II. Chemical Modifications

III. Other methods

Techniques of Bioavailability Enhancement
I. Physical Modifications
A. Particle size reduction
a. Micronization
b. Nanosuspension
B. Solubilization by surfactants
C. Co-solvency
D. Drug dispersion in carriers
a. Solid solutions
b. Eutectic mixtures
c. Solid dispersions
E. Complexation
a. Molecular encapsulation with Cyclodextrins
Techniques of Bioavailability Enhancement
II. Chemical Modifications

a. Change in the pH
b. Use of buffer
c. Derivatization
III. Other methods
a. Co-crystallization
b. Hydrotrophy
c. Solubilizing agents
d. Selective adsorption on insoluble carriers
 Micronization

 Micronization increases the dissolution rate of drugs

through increased surface area.
 Micronization of drugs is done by milling techniques
using jet mill, rotor stator colloid mills etc.
 The process involves reducing the size of the solid drug
particles to 1 to 10 microns commonly by spray drying or
by use of attrition methods (fluid energy or jet mill).The
process is also called micro-milling.

Colloidal mill
 14

Methods:
- spray drying
- air attrition methods.

E.g. : Aspirin
Griseofulvin
Steroidal compounds
Sulfa drugs
 Nanosuspension
 A pharmaceutical Nanosuspension is biphasic system consisting of Nano sized
drug particles stabilized by surfactants for either oral and topical use or parenteral
and pulmonary administration.
 This technology is applied to poorly soluble drugs that are insoluble in both water
and oils.
 The particle size distribution of the solid particles in nanosuspensions is usually
less than one micron with an average particle size ranging between 200 and 600
nm.

Ex: paclitaxel, tarazepide, amphotericin B

Techniques for the production of nano suspensions:

 a) Homogenization.
 b) Wet milling.
 Solubilization by surfactants
 Surfactants are molecules with distinct polar and nonpolar regions. Most
surfactants consist of a hydrocarbon segment connected to a polar group. The
polar group can be anionic, cationic, zwitter ionic or nonionic.

 The presence of surfactants may lower the surface tension and increase the
solubility of the drug within a solvent.

 When the concentration of surfactants is more than their critical micelle

concentration (CMC, which is in the range of 0.05–0.10% for most
surfactants), micelle formation occurs which entrap the drugs within the
micelles. This is known as micellization and generally results in enhanced
solubility of poorly soluble drugs.
2. Cosolvency
 The Solubilization of drugs in co-solvents is an another technique
for improving the solubility of poorly soluble drug.

 It is well-known that the addition of an organic cosolvent to water

can dramatically change the solubility of drugs.

 Weak electrolytes and nonpolar molecules have poor water solubility

and it can be improved by altering polarity of the solvent.

 This can be achieved by addition of another solvent. This process is

known as cosolvency. Solvent used to increase solubility known as
cosolvent.

 Cosolvent system works by reducing the interfacial tension between

the aqueous solution and hydrophobic solute. It is also commonly
referred to as solvent blending.
 e.g. Etahnol, sorbitol, glycerin, propylene glycol.
 PRODUCT COSOLVENT

Diazepam (Valium) 10% ethanol + propyline glycol

Digoxin (Lanolin) 10% ethanol + propyline glycol

Epinephrine (susphrin) 32.5% glycerin

C. Drug dispersion in carriers

a) Solid solution
b) Eutectic mixture
c) Solid dispersion
Solid solutions
 It is a binary system comprising of solid solute molecularly dispersed in a
solid solvent.

 Since the two components crystallize together in a homogeneous one phase

system, solid solutions are also called as molecular dispersions or mixed
crystals.

 Because of reduction in particle size to the molecular level, solid solutions

show greater aqueous solubility and faster dissolution than eutectics and solid
dispersion.

 They are generally prepared by fusion method where by a physical mixture of

solute and solvent are melted together followed by rapid solidification.
 Such systems, prepared by fusion, are often called as Melts

e.g. : griseofulvin - succinic acid

 The griseofulvin from such solid solution dissolves 6-7 times faster than pure
griseofulvin
Eutectic mixtures
 These systems are also prepared by fusion method.
 Eutectic melts differ from solid solutions in that the fused melts of solute-
solvent show complete miscibility but negligible solid-solid solubility.
 i.e. such system are basically intimately blended physical mixture of two
crystalline component.
 A phase diagram of two-component system is shown in diagram. When the
eutectic mixture is exposed to water, the soluble carrier dissolves leaving the
drug in a microcrystalline state which solubilizes rapidly.
 Examples of eutectics include
 paracetamol-urea,
 griseofulvin-urea,
 griseofulvin-succinic acid, etc.
 Ta and Tb are the melting point of respective solid
 sA and sB is crystal of respective solid
 24

 Disadvantage :
Not useful in :
a) Drugs which fail to crystallize from mixed melt.
b) Thermo labile drugs
c) Carrier like succinic acid decompose at their
melting point.
Solid dispersion
 These are generally prepared by solvent or co-precipitation method

 Both the guest solute and the solid carrier solvent dissolved in common

volatile liquid solvent e.g. Alcohol

 Liquid solvent is removed by evaporation under reduced pressure or freeze

drying which results in amorphous precipitation of guest in crystalline carrier.

E.g. Amorphous sulfathiazole in crystalline urea.

 The basic difference between solid dispersion and
solid solution/ eutectics is that the drug is
precipitated out in an amorphous form in the solid
dispersion while crystalline form in the solid
solution/ eutectics
Complexation

 Complexation is the reversible association between two or

more molecules to form a non bonded entity.

 Complexation relies on relatively weak forces such as van

derwaal forces, hydrogen bonding and hydrophobic
interactions.

 E.g. EDTA, polymers

 Molecular encapsulation with Cyclodextrins :
 (α-β and γ) Cyclodextrins have ability to form inclusion complexes
with hydrophobic drug having poor aqueous solubility.
 The ring has a hydrophilic exterior and lipophilic core in which
appropriately sized organic molecules can form noncovalent inclusion
complexes resulting in increased aqueous solubility and chemical
stability
 These molecules have inside hydrophobic cavity to accommodate
lipophilic drug , outside is hydrophilic.
E.g. Thiazide diuretics
Barbiturates
Benzodiazepines
NSAIDS.
Change of pH by 1 fold increase solubility by 10 fold
2) Use of buffer:
Buffer maintains the pH of the solution over time and it reduces or
eliminate the potential for precipitation upon dilution. On dilution pH
alteration occurs that decrease solubility. Change of pH by 1 fold,
increase solubility by 10 fold. If it changes by one pH unit, that
decrease ionization of the drug and solubility decreases by 10 fold.

3) Derivatization :
It is a technique used in chemistry which transforms a chemical
compound into a product of similar chemical structure, called
derivative. Derivatives have different solubility as that of adduct. It is
used for quantification of adduct formation of esters and amides via
acyl chlorides.
Other Methods
1. Co-crystallization:

 A co-crystal may be defined as a crystalline material that consists of

two or more molecular (and electrically neutral) species held together
by non-covalent forces.

 Co-crystals are more stable, particularly as the co-crystallizing agents are

solids at room temperature.

 Only three of the co-crystallizing agents are classified as generally

recognised as safe (GRAS) it includes saccharin, nicotinamide and acetic
acid limiting the pharmaceutical applications.

 Co-crystals can be prepared by evaporation of a heteromeric solution or

by grinding the components together. Another technique for the preparation
of co-crystals includes sublimation, growth from the melt, and slurry
preparation
2. Hydrotrophy:
Hydrotrophy designate the increase in solubility in water due
to the presence of large amount of additives. The
mechanism by which it improves solubility is more closely
related to complexation involving a weak interaction
between the hydrotrophic agents (sodium benzoate, sodium
acetate, sodium alginate, and urea) .
3. Solubilizing agents:
 The solubility of poorly soluble drug can also be improved by
various solubilizing materials.

 PEG 400 is improving the solubility of hydrochlorthiazide.

Modified gum karaya (MGK), a recently developed excipient
was evaluated as carrier for dissolution enhancement of poorly
soluble drug, nimodipine.

4. Selective adsorption on insoluble carriers:

 A highly active adsorbent such as inorganic clays like
Bentonite can enhance the dissolution rate of poorly water-
soluble drugs such as griseofulvin, indomethacin and
prednisone by maintaining the concentration gradient at its
maximum. Two reasons suggested for rapid release of drugs
from the surface of clays :-
1. weak physical bonding between adsorbate and adsorbent.
2. hydration and swelling of the clay in the aqueous media.
 APPLICATIONS OF SOLUBILITY:

 Solubility is of fundamental importance in a large number of scientific disciplines

and practical applications, to the use of medicines, and the transport of pollutants.
 Solubility is represents a fundamental concept in fields of research.
 The solubility of a substance becomes especially important in the pharmaceutical
field because it often represents a major factor that controls the bioavailability of a
drug substance.
 Solubility is commonly used to describe the substance, to indicate a substance's
polarity, to help to distinguish it from other substances, and as a guide to
applications of the substance.
 Moreover, solubility and solubility-related properties can also provide important
information regarding the structure of drug substances, and in their range of
possible intermolecular interactions.
 CONCLUSIONS:
 A drug administered in solution form immediately available for absorption.
 Solubility is a most important parameter for the oral bioavailability of poorly
soluble drugs.
 Dissolution of drug is the rate determining step for oral absorption of the poorly
water soluble drugs, which can subsequently affect the in vivo absorption of drug.
 Currently only 8% of new drug candidates have both high solubility and
permeability.
 Because of solubility problem of many drugs the bioavailability of them gets
affected and hence solubility enhancement becomes necessary.
 It is now possible that to increase the solubility of poorly soluble drugs with the
help of various techniques.
 REFERENCES:
 Sink PJ. Martin’s physical pharmacy and pharmaceutical sciences, 5th edition, B
& I publications pvt .ltd, Noida, 2006.
 Lachman L, Liebermann HA, Kiang Jl. The theory and practice of industrial
pharmacy, 3rd edition, Varghese publishers, Mumbai 1991.
 Lieberman HA, Lachman L, Schwartz JB.phamacetical dosage pharms: tablets
vol.I-III, 2ndedition, CBS publishers&distributers, New Delhi, 2005.
 Biopharmaceutics and pharmacokinetics –A treatise. D.M Bramhmkar .Sunil
B.Jaiswal.
 International journal of pharmaceutical research and development (IJPRD),
solubility enhancement techniques for poor solubility drugs: a review. Mahesh. I,
limbachiya, vol (04); june2012 (071-186)